Cabozantinib with nivolumab for untreated advanced renal cell carcinoma

The committee's preferred assumptions included:

• a state transition model considering 4 lines of treatment followed by best supportive care

• UK real-world evidence used to inform the underlying risk and safety associated with having renal cell carcinoma and having treatment

• an indirect comparison was used to compare to other treatments for renal cell carcinoma

• network meta-analyses applied to the baseline risk to calculate the effectiveness and safety of other treatments in the pathway

• using time-varying hazards using a fractional polynomial network meta-analysis to calculate the effectiveness of all treatments at first line, including cabozantinib with nivolumab

• assumptions that some outcomes could be used as surrogates for other outcomes, such as progression-free survival for time to stopping treatment or time to next treatment

• applying utility values previously accepted in NICE technology appraisals to capture patient health-related quality of life as their disease progresses and they have multiple lines of treatment.

The company explained where their preferred analysis differed from the committees. The company preferred:

• the model to only consider 2 lines of treatment followed by best supportive care, instead of 4 lines

• using a proportional hazards network meta-analysis to calculate the effectiveness of all treatments at first line, including cabozantinib plus nivolumab, instead of the time-varying hazard fractional polynomial approach

• an assumption that time to stopping treatment be equal to progression-free survival, instead of using time to stopping treatment data from the UK real-world evidence

• using safety data from individual trials and performing a naive comparison, instead of the indirect treatment approach.

The committee considered the severity of the condition (the future health lost by people living with the condition and having standard care in the NHS). The committee may apply a greater weight to quality-adjusted life years (QALYs) if technologies are indicated for conditions with a high degree of severity (a severity modifier). The committee considered absolute and proportional QALY shortfall estimates in line with NICE's manual on health technology evaluation. It noted that the severity of the condition depends on which treatment is considered standard care, and there are a range of treatments recommended for untreated advanced renal cell carcinoma. The committee was presented with 3 options for assessing whether a severity weighting applied. These were fully incremental analyses, pairwise analyses (in which the most appropriate comparator was defined), and a weighted market share approach. For the pairwise comparison, the committee considered the most appropriate comparators to be the other combination treatments of nivolumab plus ipilimumab and pembrolizumab plus lenvatinib in the intermediate- or poor-risk subgroup. The committee noted that the absolute or proportionate QALY shortfall thresholds were unlikely to be met using any of the 3 options, or when considering the most appropriate comparators in each risk group, so a severity modifier was not applied.

Because of confidential commercial arrangements for cabozantinib, nivolumab, and other comparators, the cost-effectiveness results cannot be reported here. The committee considered the cost-effectiveness results when using the EAG base case and company preferred assumptions. The committee was also presented with a range of scenarios investigating the impact of different assumptions. When considering the all-risk group or favourable-risk subgroup, the cost-effectiveness estimates for cabozantinib plus nivolumab compared with available treatments were above what NICE normally consider a cost-effective use of NHS resources in both the EAG's and company's base cases. When considering the intermediate- and poor-risk subgroup, the committee concluded that none of the analyses reflected its preferences so it could not make a recommendation. The committee agreed that, to recommend cabozantinib plus nivolumab, it would have to represent good value for money compared with both nivolumab plus ipilimumab and pembrolizumab plus lenvatinib. This is because NICE's technology appraisal guidance on pembrolizumab with lenvatinib for untreated advanced RCC specifies that it should only be offered if they would otherwise have offered nivolumab plus ipilimumab. The committee would have preferred to see an indirect treatment comparison including updated intermediate- and poor-risk progression-free survival data for pembrolizumab plus lenvatinib. If this is not available, the committee would prefer to see alternative methods used to include pembrolizumab plus lenvatinib in the indirect treatment comparison. The committee would also like to see further scenarios and additional data to help explore and validate the modelled results for nivolumab plus ipilimumab.

The committee heard that some people may have difficulty accessing healthcare or rely on carers to assist them, so may struggle to travel to hospital for regular infusions. The committee commented that these are not equality issues that can be addressed by NICE technology appraisal recommendations. However, the committee considered that it had not seen any information indicating that cabozantinib plus nivolumab would increase access to treatment. The committee did not identify any other equality issues.

The committee considered if cabozantinib plus nivolumab was innovative. The committee saw no evidence that cabozantinib plus nivolumab lessened the psychological impact of renal cell carcinoma more than other available treatments, so expected this to be captured in the economic modelling. It did not identify additional benefits of cabozantinib plus nivolumab not captured in the economic modelling. The committee concluded that the benefits of cabozantinib plus nivolumab were taken into account in the cost-effectiveness results.

The committee concluded that cabozantinib plus nivolumab is an effective treatment for renal cell carcinoma. But the analyses either showed that cabozantinib plus nivolumab was not cost effective, or did not reflect the committee's preferred assumptions, when compared with the most appropriate comparators in each risk group. So, cabozantinib plus nivolumab is not recommended for untreated advanced renal cell carcinoma in adults.